A phase I study of silibinin in hormone refractory prostate cancer

Flaig, Thomas W.; Agarwal, Raksheeth; Su, Lih-Jen; Harrison, Gail Singer; Gustafson, Daniel L.; Glodé, L. Michael

doi:10.1200/jco.2005.23.16_suppl.4698

Cited by 11 publications

(12 citation statements)

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“…This conclusion is consistent with the result of the original evaluation of silipide in human volunteers (12), and a similar inference was made in a preliminary report of a current phase I study of silibinin in hormone-refractory prostate cancer patients, in which up to 20 g silibinin was administered orally daily for a month (32). We describe here for the first time the identification of silibinin plasma metabolites and measurement of silibinin tissue levels in humans who ingested silibinin.…”

Section: Discussionsupporting

confidence: 76%

Pilot Study of Oral Silibinin, a Putative Chemopreventive Agent, in Colorectal Cancer Patients: Silibinin Levels in Plasma, Colorectum, and Liver and Their Pharmacodynamic Consequences

Hoh

Boocock

Marczylo

et al. 2006

Clinical Cancer Research

152

141

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Silibinin, a flavonolignan from milk thistle, has intestinal cancer chemopreventive efficacy in rodents. It is a strong antioxidant and modulates the insulin-like growth factor (IGF) system by increasing circulating levels of IGF-binding protein 3 (IGFBP-3) and decreasing levels of IGF-I.Here, the hypothesis was tested that administration of oral silibinin generates agent levels in human blood and colorectal and hepatic tissues consistent with pharmacologic activity. Patients with confirmed colorectal adenocarcinoma received silibinin formulated with phosphatidylcholine (silipide) at dosages of 360, 720, or 1,440 mg silibinin daily for 7 days. Blood and biopsy samples of normal and malignant colorectum or liver were obtained before dosing, and blood and colorectal or hepatic tissues were collected at resection surgery after the final silipide dose. Levels of silibinin were quantified by high-pressure liquid chromatography-UV, and plasma metabolites were identified by liquid chromatography-mass spectrometry. Blood levels of IGFBP-3, IGF-I, and the oxidative DNA damage pyrimidopurinone adduct of deoxyguanosine (M 1 dG) were determined. Repeated administration of silipide was safe and achieved levels of silibinin of 0.3 to 4 Amol/L in the plasma, 0.3 to 2.5 nmol/g tissue in the liver, and 20 to 141nmol/g tissue in colorectal tissue. Silibinin monoglucuronide, silibinin diglucuronide, silibinin monosulfate, and silibinin glucuronide sulfate were identified in the plasma. Intervention with silipide did not affect circulating levels of IGFBP-3, IGF-I, or M 1 dG. The high silibinin levels achieved in the human colorectal mucosa after consumption of safe silibinin doses support its further exploration as a potential human colorectal cancer chemopreventive agent.

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Section: Discussionsupporting

confidence: 76%

Pilot Study of Oral Silibinin, a Putative Chemopreventive Agent, in Colorectal Cancer Patients: Silibinin Levels in Plasma, Colorectum, and Liver and Their Pharmacodynamic Consequences

Hoh

Boocock

Marczylo

et al. 2006

Clinical Cancer Research

152

141

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“…Preliminary results of this study have been reported in abstract form, indicating that at daily doses of 5 to 20 g, peak blood concentrations of >100 lM were achieved in some patients from 30 to 60 min after dosing. 38 This high-dose regimen is in contrast to a recent pharmacokinetic study of standard dose silibinin (1.4 g daily) in colorectal cancer patients, which demonstrated that measurable tissue levels were achievable at that dosing level, with a terminal plasma half-life of 3.4 hr. 39 Although, preclinical data would support the use of silibinin in combination with doxorubicin, cisplatin and carboplatin, these agents are not commonly used in the treatment of prostate cancer.…”

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confidence: 72%

Silibinin synergizes with mitoxantrone to inhibit cell growth and induce apoptosis in human prostate cancer cells

Flaig

Harrison

et al. 2007

Intl Journal of Cancer

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The purpose of these experiments was to assess the synergistic activity of silibinin with chemotherapy agents in clinical use against prostate cancer. Silybin-phytosome, a commercially available formulation containing silibinin, has recently been studied in a phase I clinical trial. The silibinin doses used in the present study are clinically achievable based on the preliminary phase I data. DU145, PC-3 and LNCaP prostate cancer cells were seeded in 96-well plates in triplicate. Twenty-four hours later, silibinin (10, 20 and 40 lM) and either mitoxantrone or docetaxel were added to the designated wells. Seventy-two hours post-treatment, cell viability was determined with a tetrazolium-based assay. The combination index (CI) for determination of a synergistic effect was calculated, with values of <0.9 indicating synergy and values >1.1 antagonism. Apoptosis was also assessed using a luminescent assay after 72 hr of treatment with media alone, silibinin, mitoxantrone, or silibinin plus mitoxantrone. Silibinin showed a synergistic effect with mitoxantrone, as measured by reduction in cell viability. The CI values ranged from 0.413 to 2.650 for the combination of silibinin and mitoxantrone; in contrast, treatment with docetaxel and silibinin showed little or no synergy, with CI values of 0.898-4.469. In concordance with these findings, the addition of silibinin increased the level of apoptosis compared to mitoxantrone alone, particularly in the PC-3 cells. The combination of silibinin and mitoxantrone exhibits a pattern of synergy in reducing cell viability with increased apoptosis. These data are important in the planning of future clinical applications of silibinin. ' 2007 Wiley-Liss, Inc.Key words: silibinin; mitoxantrone; docetaxel; prostate cancer Prostate cancer is the most common non-skin cancer diagnosed in men. In 2005, the American Cancer Society estimates that 232,000 men were diagnosed and 30,000 died from prostate cancer in the United States. 1 Early stage or organ confined cases may be cured with surgical prostatectomy or radiation therapy, although, some low-risk patients may also choose watchful waiting. 2,3 Disease that has spread beyond the prostate is generally first treated with hormonal ablation. The addition of cytotoxic chemotherapy is used in selected hormone-refractory patients, with this approach demonstrating a small ( 2 month) survival advantage. 4,5 Milk thistle (Silybum marianum) has a long history of use in humans and is commonly used in the treatment of liver disease. 6,7 Silymarin, the name of the crude milk thistle extract, is composed of several stereoisomers including silibinin (or silybin), silychristin and silydianin. 8 Silibinin and silymarin have been shown to inhibit in vitro cell growth in several cancer models including prostate, 9-11 bladder, 12,13 colon, 14,15 breast, 16,17 cervical, 18 skin 19,20 and lung cancer. 21,22 Additional in vivo experiments have demonstrated an anti-cancer effect of silibinin and silymarin in models of prostate, 23 skin, 24,25 bladder 26 and col...

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“…20 A phase I study in men with prostate cancer found that administration of silibinin-phytosome (Siliphos) was well tolerated; however, gastrointestinal toxicities were observed at elevated doses. 47 Grade 1 or 2 hyperbilirubinemia was observed at a dose of 15 g/d or higher. Grade 1, 2, and 3 elevations in AST and ALT were also observed at 13 g/d and higher.…”

Section: Adverse Eventsmentioning

confidence: 99%

“…A phase I study of silibinin in treating hormone refractory prostate cancer showed that it is possible to achieve biologically active blood levels using silibinin powder mixed in apple sauce. 47 Of note, a case report described a 52-year-old man with unresectable biopsy-proven hepato cellular carcinoma. 48 The patient began taking 450 mg of silymarin per day, and spontaneous regression of the tumor was reported in the absence of initiation of anticancer therapy.…”

Section: Direct Anticancer Effectsmentioning

confidence: 99%

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Clinical Applications of Silybum marianum in Oncology

Greenlee

Abascal²,

Yarnell

et al. 2007

Integr Cancer Ther

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Milk thistle (Silybum marianum) is an herb that is increasingly used in oncology research and treatment settings. Historically, it has been used to treat liver and biliary disorders and has been used in detoxification and cleansing protocols. However, milk thistle is increasingly being investigated for its use in adult and pediatric populations for oncology indications. Possible indications during cancer treatment include cleansing and detoxification after chemotherapy, preventing hepatotoxicity during chemotherapy, treating hepatotoxicity after chemotherapy, and potentiating chemotherapy and radiation therapy as an adjunctive treatment. Milk thistle (Silybum marianum [L.] Gaertn., plant family Asteraceae) seed is an herb commonly used by Western herbalists and naturopathic physicians to treat liver disorders in adults. The German Commission E currently recommends its use for dyspeptic complaints, toxin-induced liver damage, and hepatic cirrhosis and as a supportive therapy for chronic inflammatory liver conditions. 1 However, milk thistle is increasingly used in research and clinical practice in adult and pediatric populations in the oncology setting. It is being used for detoxification after chemotherapy, as a hepatoprotectant during chemotherapy, as an adjunct to cancer treatment, and to ameliorate long-term effects of cancer treatment. Researchers are actively investigating its role as a chemopreventive agent and possible treatment of cancer.Much of milk thistle's current clinical use is based on recent research on the actions of silymarin, milk thistle's flavonoid complex. The plant in its whole form, however, has a long history of use that has not been fully explored. In its native Mediterranean region, it has been used for liver ailments since the Greco-Roman era, and today it remains in folk use as a digestive aid, aperient, anti-inflammatory, antineoplastic, hypotensive, styptic, diuretic, and general tonifier.2 Other confirmed folk applications include its use for pruritus, hemorrhoids, colic, malaria, and psoriasis, and as a galactagogue.3 Milk thistle traveled to North America with the Europeans and was used by North American physicians to treat gallstones, vomiting in pregnancy, amenorrhea, uterine hemorrhage, hematuria, painful dysuria, and congestion of the liver, spleen, or kidneys. 2One of the more recent directions of milk thistle research is its use in oncology. Silymarin and silibinin (1 of the components of silymarin, also called silibin or silybin) have been evaluated for their ability to exert direct cytotoxic effects, mitigate toxicity of certain anticancer agents, and enhance the efficacy of chemotherapeutic agents. Milk thistle is increasingly used as an adjunct treatment for many types of cancer, with recent research also suggesting cancer prevention applications.In this article we describe current and potential clinical applications of milk thistle in the oncology setting. Milk thistle use is usually based on historical indications. Very little clinical research has been conducted in ...

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A phase I study of silibinin in hormone refractory prostate cancer

Cited by 11 publications

References 0 publications

Pilot Study of Oral Silibinin, a Putative Chemopreventive Agent, in Colorectal Cancer Patients: Silibinin Levels in Plasma, Colorectum, and Liver and Their Pharmacodynamic Consequences

Pilot Study of Oral Silibinin, a Putative Chemopreventive Agent, in Colorectal Cancer Patients: Silibinin Levels in Plasma, Colorectum, and Liver and Their Pharmacodynamic Consequences

Silibinin synergizes with mitoxantrone to inhibit cell growth and induce apoptosis in human prostate cancer cells

Clinical Applications of Silybum marianum in Oncology

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